tbuckley/cabot-search huggingface dataset:
MODL-18. ESTABLISHMENT OF A NOVEL HUMANIZED PERIPHERAL BLOOD MONONUCLEAR CELL (HU-PBMC) MOUSE MODEL TO EVALUATE LYMPHOCYTE INVOLVEMENT IN GLIOBLASTOMA AND ITS TREATMENT
Authors: Krutika Deshpande, Denna Kwang, Marvin Cadiente, Jasmine Delany, Taufeeq Ahmed, Bailey McDonald, Xi Wang, Anne Marie Barrette, Dongxu Sun
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) has traditionally been classified as an ‘immune cold’ tumor, characterized by strong immunosuppression, low mutational burden, and few presentable antigens. However, lack of standard-of-care improvement and the discovery of targetable immune-modulatory biomarkers like PD-1/PD-L1 and CTLA4 in the GBM microenvironment has prompted clinical trials to explore immune checkpoint inhibition (ICI) efficacy in patients, with moderate responses in specific patient subsets. To better characterize ICI in GBM, and to match prospective patients to suitable therapeutics, it is necessary to establish preclinical GBM mouse models that incorporate the lymphocytic milieu as xenograft and syngeneic models are unable to replicate the immune responses seen in humans. We have established a novel humanized PBMC mouse model that recapitulates human GBM pathology in the brain, supports and maintains systemic and intracranial human T cell engraftment in the presence of GBM tumors, and allows for a suitable timeline for preclinical testing of therapeutics prior to onset of GVHD. In our study, orthotopic GBM-bearing NSG mice showed successful human CD45+ engraftment in the blood (~20%) and brain (~5%) 2 weeks post intravenous implantation of hu-PBMCs. Restricted tumor growth was observed, indicating initial responsiveness of human immune cells to GBM. Engraftment remained unaffected upon treatment with temozolomide (GBM standard of care), and persisted over 6 weeks (brain ~40%, blood ~70%) before GVHD onset (week 7). ~90% of the hCD45+ population was CD3+, indicating robust T cell engraftment, which was further characterized into CD4+ and CD8+ subsets and by activation status (HLA-DR, CD45RA/RO, PD-1, FOXP3 etc) within the tumor-bearing brain and blood. Anti-PD-1 inhibitor efficacy was also tested in engrafted animals to observe ICI potential in GBM. This humanized mouse provides a powerful translational model to evaluate T cell responses in tumor pathology and immunotherapy in GBM and potentially other primary or secondary brain malignancies.
CTNI-45. UPFRONT CHEMOTHERAPY AND SUBSEQUENT RESECTION UTILIZING NEOADJUVANT STRATEGY FOR OLIGODENDROGLIOMAS
Authors: Hikaru Sasaki, Yohei Kitamura, Masahiro Toda, Yuichi Hirose
Journal: Neuro-Oncology (2023)

Abstract Although both of functional preservation and higher extent of resection are required in glioma surgery, maximal resection with the risk of functional sequela is uniformly performed regardless of tumor pathology and treatment sensitivity in the current practice. Oligodendrogliomas are known to be associated with relatively favorable prognosis, however, many patients still eventually succumb to death due to tumors. Improvement in the long-term survival rate and functional preservation would be the next step to be achieved. In our hospital, patients with 1p/19q-codeleted glioma have been treated by upfront chemotherapy, if deemed in need of adjuvant treatment after initial resection, since 2006. If the initial resection was incomplete, the second surgery was intended following tumor volume decrease by chemotherapy (second-look resection, SLR). Intentional staged resection was performed in several cases for whom presence of 1p/19q codeletion was strongly suggested based on preoperative imaging characteristics. Utility of this strategy was evaluated. Forty-one patients with 1p/19q-codeleted glioma have been treated with the strategy. Of these, 30 were grade 2, and 11 were grade 3 tumors. In 9 of the 41 cases, radiotherapy was prescribed immediately after chemotherapy or SLR. Median tumor volume decrease rate by chemotherapy in the cases with initial incomplete resection was -35%. SLR following tumor volume decrease was performed in 22 cases. Median progression-free survival and overall survival after the initiation of chemotherapy were 81 months and 175 months for each in both of the total 41 cases and 32 cases for whom radiotherapy was deferred. Most of the recurrence occurred in the residual FLAIR high intensity. Upfront chemotherapy and subsequent resection strategy utilizing chemotherapeutic response provides more precise resection as well as reduction of resection volume as compared with one-time maximal safe resection. Radiotherapy may be indicated for the cases with residual FLAIR abnormality after chemotherapy or SLR.
IMMU-42. PP2A-INHIBITION INDUCES STING-TYPE I-MEDIATED IMMUNOLOGIC CELL DEATH IN GBM
Authors: Isha Mondal, Oishika Das, Rongze Olivia Lu, Winson Ho
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is one of the most lethal forms of brain cancer, and is known to be an aggressive, immunologically cold tumor, resulting in a lack of T-cell infiltration and killing. Thus increasing immune-mediated killing of GBM is a promising therapeutic method. Our group has found that Protein Phosphatase 2A (PP2A), a ubiquitous serine/threonine phosphatase that has been shown to enhance tumor immunogenicity in glioblastoma, does so by inducing immunogenic cell death. We used LB-100, a small molecule inhibitor of the catalytic subunit of PP2A, as a promising drug-therapy. CRISPR-KO of PP2A was generated in murine glioma lines GL261 and SB28. Markers of immunologic cell death, such as calreticulin, gamma-H2AX, and HMGB1 were assessed. In vitro, western blotting of SB28 and GL261 showed significantly increased expression of gamma-H2AX in PP2A-KO compared to WT. Flow-cytometry staining of SB28 and GL261 revealed a dramatic increase in calreticulin expression in PP2A-KO compared to WT. An antibody-based fluorescence assay for HMGB1 also showed dramatic increase in PP2A-KO compared to WT. All experiments were repeated by treating LB-100 for 24 hour to SB28 and GL261 WT and PP2A-KO cells, and revealed a dose-dependent increase in expression of immunogenic cell death markers. In vivo, B6 mice were injected intracranially with SB28 WT or PP2A-deficient tumor and monitored till endpoint. At the endpoint, tumors were harvested, cryosectioned, and stained for calreticulin and gamma-H2AX. Mice injected with PP2A-KO tumor survived longer than WT, and had the highest expression of both calreticulin gamma-H2AX when compared to WT tissue. In conclusion, PP2A-deficiency and inhibition via LB-100 is demonstrated to induce immunogenic cell death in tumors, thus being a promising target for immunotherapy.
INNV-35. IMPLEMENTATION OF A NATIONAL ADOLESCENT AND YOUNG ADULT MOLECULAR TUMOR BOARD: REPORT FROM THE CANADIAN AYA NEURO-ONCOLOGY NETWORK
Authors: Mary-Jane Lim-Fat, Sunit Das, Seth Climans, Maria MacDonald, Sébastien Perreault, Stephen Yip, Rebecca Harrison, Sarah Lapointe, Aimee Chan, Natalie Massey, Craig Erker, Mary MacNeil, Sarah Ironside, Derek Tsang, Cynthia Hawkins, Uri Tabori, Julie Bennett
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The adolescent and young adult (AYA) population (15-39 years) is a unique and understudied population and their care requires multidisciplinary expertise. Current challenges in AYA neuro-oncology include fragmented care across pediatric and adult hospitals, low inclusion in clinical trials, unique survivorship considerations and a lack of standard-of-care therapies for this population. METHODS We will report on a two-and-a-half-year national effort from the Canadian AYA Neuro-Oncology Network (CANON) to implement national clinical and molecular AYA rounds. The aims of the rounds are to provide a platform for standardized diagnostics and multidisciplinary recommendations benefiting from the expertise of pediatric and adult providers across several tertiary and community centers. RESULTS Since April 2021, the Canadian national AYA rounds have occurred biweekly on a virtual secure platform. As of April 2023, 132 cases have been discussed from 25 sites; 15 cases (11%) involved pediatric patients and 117 (89%) were patients aged &amp;gt; 18 and treated at adult hospitals. Cases discussed included adult (n =34, 26%) and pediatric type (n = 22, 17%) low-(n=25, 19%) and high-grade (n=30, 23%) glioma, medulloblastoma (n=14, 10.5%), ependymoma (n=6, 5%) and other tumors (glioneuronal tumors, pineal tumors, germinoma). A total of 175 providers and 70 trainees across 32 Canadian institutions have attended the rounds, spanning adult and pediatric neurosurgery, neuropathology, neuro-oncology, radiation oncology and radiology. The updated results of an ongoing prospective database of cases presented at our AYA rounds, outlining themes around molecular characterization, choice of therapies and relevant clinical outcomes will be presented at the meeting. CONCLUSIONS Virtual national AYA-neuro-oncology multi-disciplinary rounds is an effective platform that has raised awareness of current gaps and has facilitated nation-wide solutions to improve the care of AYA brain tumors, leveraging research and clinical collaborations.
EXTH-77. EXTENDED HALF-LIFE IL-2 SYNERGIZES WITH Α-PD-1 FOR TREATMENT OF PRECLINICAL MURINE GLIOBLASTOMA MODELS
Authors: Carley Owens, Zachariah Tritz, Katayoun Ayasoufi, Delaney Wolf, Ian Parney, Michael Hanson, Jin Fang, Aaron Johnson, Jian Campian, Cori Fain, Benjamin Himes, Courtney Malo, Emma Goddery, Lila Yokanovich, Chensu Wang, Richard Vile, Kelly Moynihan, Darrell J Irvine, Rosa Mercano, Dane Wittrup, Mark Maynes
Journal: Neuro-Oncology (2023)

Abstract α-PD-1 checkpoint blockade is a promising immunotherapeutic approach for many solid tumors; however, this strategy is minimally effective for GBM patients as a monotherapy. One potential reason why α-PD-1 checkpoint blockade is ineffective is the tumor microenvironment and systemic derangements of the immune system which are prevalent in GBM patients. We have successfully modeled peripheral immune derangements in experimental murine GBM models. These include low peripheral blood CD4 T cell counts, reduced MHC class II expression on monocytes, and atrophy of primary immune organs in animals harboring gliomas. We therefore hypothesized that extended half-life IL-2, a potent cytokine which promotes the proliferation, differentiation, and killing activity of T cells, could overcome immune derangements and could potentially synergize with α-PD-1 checkpoint blockade therapy. In cohorts of C57Bl/6 mice, we supplemented α-PD-1 checkpoint blockade with multiple bio-engineered extended half-life IL-2 molecules to treat GL261 and CT2A orthotopic glioma models which are normally resistant to monotherapy. We observe a statistically significant increase in survival in GL261-bearing animals receiving the combination of extended half-life IL-2 reagents and αPD-1 therapy relative to control-treated mice. Some animals receiving this combination therapy had a reduction in tumor burden to levels below detection. These long-term survivors underwent a rechallenge experiment with a second inoculation of GL261-Luc and effectively cleared tumor without further therapeutic intervention. This intervention causes a significant shift in the immune profile, including the formation of mature T cell responses, as well as restoring the diminished peripheral immune cell counts in GL261-bearing animals. Finally, combining extended half-life IL-2 with α-PD-1 checkpoint blockade is effective independently of the CD8 T cell response. Together, these data suggest that combination immunotherapies employing extended half-life IL-2 fusion proteins are translational to the clinic and do not require the identification of tumor specific antigens for efficacy
CTNI-28. FINAL RESULTS OF A PILOT STUDY TO EVALUATE INFUSION RATE ESCALATION TO MAXIMIZE VOLUME OF DISTRIBUTION DURING CONVECTION ENHANCED DELIVERY TO CONTRAST-ENHANCING GLIOBLASTOMA
Authors: James Liu, Nam Tran, Cecily Piteo, Sebastian Matzza, Peter Forsyth, Michael A Vogelbaum
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Volume of distribution (Vd) during convection enhanced delivery is impacted by the characteristics of the tissue being treated. For Glioblastoma (GBM), Vd is substantially higher in non-contrast enhancing tumor than in contrast enhancing tumor due to higher infusate efflux in enhancing tumor. We hypothesized that increasing the infusion rate could overcome the infusate efflux rate in enhancing tumor to improve the Vd to volume of infusion (Vi) ratio and provide better tumor coverage. METHODS A single center, IRB-approved pilot study was conducted under an IND (held by MAV) to perform rate escalated delivery of Topotecan with Gadolinium-DTPA to contrast-enhancing recurrent GBM (rGBM). A single Cleveland Multiport Catheter was surgically placed into enhancing tumor and then a 4-hour infusion was performed with real-time MRI visualization. Intra- and inter-patient rate escalation was performed. RESULTS 3 patients with rGBM were enrolled and treated. The initial infusion rate for patient 1 was 5 microliters/minute per microcatheter (4 total) and the final infusion rate for the third patient was 20 microliters/minute per microcatheter. We observed partial backflow at this rate and so did not escalate higher. There was coverage of both enhancing and non-enhancing tumor in all cases, and the Vd/Vi ratio ranged from 0.7 to 1.3. Patients tolerated the treatments well; there were no CTCAE Grade 3 or higher treatment related adverse events. CONCLUSIONS The higher efflux rate associate with contrast-enhancing tumor tissue can be overcome with sufficient infusion rate escalation.
NIMG-25. CLINICAL FEASIBILITY OF AI-BASED T2 FLAIR SEGMENTATION FOR DETECTION OF PROGRESSION IN NON-ENHANCING LOWER GRADE GLIOMA
Authors: Tracy Luks, Pablo Damasceno, Tyler Gleason, James Hawkins, Lauro Avalos, Shawn Hervey-Jumper, Sharmila Majumdar, Janine Lupo, Jason Crane, Javier Villanueva-Meyer
Journal: Neuro-Oncology (2023)

Abstract Radiological assessment of progression in patients with non-enhancing lower grade gliomas (LrGG: grade 2 and 3) is primarily based on increase in lesion size on anatomical T2-weighted fluid-attenuated inversion recovery (T2 FLAIR) magnetic resonance imaging (MRI) sequences. We evaluated whether an AI-based method could be used routinely as part of patient care to assist in detecting non-enhancing glioma progression. The software offers the ability for real-time quality control and editing, choice of baseline exam and threshold for progression, and shows 3D image segmentations side-by-side with lesion volume graphs. The model was trained to create T2 FLAIR abnormality segmentations. The 515 training images included pre-surgical scans of newly diagnosed and recurrent patients, and post-surgical surveillance scans of patients. Clara Deploy was used for inference and to handle communication between PACS and an XNAT server, where results were stored and displayed. Following RANO criteria, lesions were marked as ‘progressed’ if volume changes were larger than 40% between baseline and the MRI of interest. The 124 AI-based segmentation model test volumes were compared to manual segmentation volumes, and achieved a mean DICE score of 0.87 ± 0.20. The sensitivity and specificity of the RANO progression assessment based on the model was compared with RANO progression assessment based on manual segmentation in 16 patients (6 serial MRIs each), with 85% sensitivity, 82% specificity. This work presents the first steps toward clinical deployment of AI-based real-time quantitative detection of LrGG progression by RANO criteria. This quantitative assessment provides supplementary information to the radiologist and can be shared with the patient’s neuro-oncologist, neurosurgeon, and other clinical team members for consideration in treatment planning.
DDEL-12. A CONFORMABLE IMPLANTABLE DEVICE - MICROMESH - FOR THE SUSTAINED DELIVERY OF CHEMOTHERAPEUTIC MOLECULES AND IMMUNE CHECK POINT INHIBITORS AGAINST HIGH-GRADE GLIOMAS
Authors: Anna Lisa Palange, Irene Guerriero, Cristiano Pesce, Daniele Di Mascolo, Paolo Decuzzi
Journal: Neuro-Oncology (2023)

Abstract High-grade gliomas, like glioblastoma (GBM), continue to have a poor prognosis with therapeutic options limited to maximal safe resection and adjuvant radiochemotherapy. Effective treatment is hampered by the blood-brain barrier, limiting the intratumor permeation of systemically administered agents; and biological heterogeneity of malignant cells, requiring complex therapeutic regimens. A conformable, compartmentalized polymeric implant – microMESH – has been engineered to overcome these obstacles by realizing a localized, sustained release of drugs, small inhibitors, antibodies, and nanomedicines. In the present configuration, microMESH comprises a water-soluble polyvinyl alcohol microlayer, loaded with the immune checkpoint aCD47, intercalated with a microfabricated network of poly lactic-co-glycolic acid, carrying docetaxel (DTXL). Upon deposition over the tumor margins, microMESH adheres and conforms to the local tissue releasing thereof its therapeutic cargo for several weeks, circumventing possible systemic toxicity. Gel permeation chromatography, nuclear magnetic resonance spectroscopy, weight and pH variations were measured to assess the microMESH biodegradation over time. microMESH biocompatibility and cytotoxicity were assessed on cancer cell monolayers and spheroids. The preclinical performance of microMESH was evaluated in two syngeneic mouse models of high-grade gliomas obtained via the intracranial inoculation of murine cancer cells – CT-2A, cold tumor; GL261, hot tumor. Flow cytometry was used to map the immune component in the tumor and assess the expression of immune checkpoints. Bioluminescence imaging was used to monitor tumor proliferation longitudinally. microMESH biodegraded in ~2 months with no documented toxicity. Preliminary experiments with an aCD47/DTXL–microMESH applied over the unresected margins of an orthotopic CT-2A model documented a median overall survival of 33.5 days against 18 days for untreated mice, 22 days for intravenously injected DTXL, 24 days for intraperitoneally administered aCD47 (statistically not significant difference among the control groups). microMESH allowed the sustained delivery of complex combination therapies directly at the tumor bed demonstrating superior efficacy over systemic therapies.
EPCO-14. IDENTIFYING EPIGENETIC VULNERABILITIES OF MINIMAL RESIDUAL DISEASE IN GLIOBLASTOMA USING IN VIVO CRISPR SCREENS
Authors: Kelly Mitchell, Anca Mihalas, Sonali Arora, Patrick Paddison, Anoop Patel
Journal: Neuro-Oncology (2023)

Abstract Therapy for glioblastoma (GBM) includes surgical resection, radiation, and chemotherapy, which functionally reduces tumor burden to a state of minimal residual disease (MRD). However, recurrence over time is universal. Large-scale longitudinal studies of GBM patient samples did not identify selection pressure for specific DNA mutations in recurrent disease, highlighting the importance of epigenetic mechanisms during relapse. In this study, we aim to model MRD and the functional and transcriptional effects of epigenetic perturbations in GBM patient derived xenografts (PDXs). We developed an in vivo inducible genome editing system by engineering 827 GBM stem cells to express doxycycline inducible Cas9 and a pool of 14 CRISPR sgRNAs targeting 5 epigenetic factors (readers/erasers of H3K27me3 and H4 acetyltransferase KAT5) and controls. Tumor cells are implanted orthotopically and mice are followed by serial MRIs until tumor volumes reach 2mm3, after which in vivo editing is induced by administration of doxycycline. Cells are harvested for scRNA-sequencing and targeted amplification of sgRNA libraries, allowing for assignment of sgRNAs to individual cells. Genome editing efficiencies ranged from 50-90% in vivo. Knockout of core Polycomb (PcG) complex members led to dysregulated expression of genes involved in therapeutic resistance and altered cell state distributions. Current directions include optimization of sgRNA targeting and recovery of CRISPR-edited cells from tumors for scaling up screens. In addition, we have developed a “standard of care” treatment regimen in GBM PDX models whereby temozolomide and radiation therapy is dose optimized to achieve a latent state that mimics MRD followed by eventual tumor recurrence. Future experiments will combine MRD modeling in PDXs with in vivo CRISPR screening to characterize functional dependencies of MRD in GBM. This data provides proof of concept for utilizing these tools for studying genotype to phenotype connections in a complex GBM model system.
EPID-23. FACILITY VOLUME STATUS IS PREDICTIVE OF SURVIVAL AND TREATMENT RECOMMENDATIONS IN PATIENTS WITH INTRACRANIAL MENINGIOMA
Authors: Nolan Brown, Sachiv Chakravarti, Cathleen Kuo, Zachery Neil, Oanh Nguyen, Yusuf Mehkri, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION There is a growing body of evidence demonstrating improved survival outcomes for patients with CNS neoplasms who are treated at high volume facilities (HVFs) as compared to low volume facilities (LVFs). METHODS The National Cancer Database (NCDB) was queried for adult patients who sought treatment for intracranial meningioma between 2004 and 2019 at one of 1,500 Commission on Cancer-accredited facilities. Data reported included patient sociodemographic information, patient comorbidity status, and relevant tumor characteristics. After patients were stratified by facility volume, the Mann-Whitney U and Fisher exact tests were used for bivariate analysis of both continuous and categorical variables. Multivariate Cox proportional hazard model and log-rank test were used to determine whether there was any association between facility volume and overall survival. RESULTS In total, 336,115 patients diagnosed with meningioma were included; 23,207 (6.9%) patients were treated at an HVF and 312,908 (93.1%) patients were treated at an LVF. On bivariate analysis, patients covered by private insurance were more likely to have been treated at an HVF (50.9% vs 36.8%, p=0.0043). Furthermore, with respect to county-based geographic trends, patients treated at HVFs were more likely to reside in an urban area (14.5% vs 11.6%, p=0.027). With respect to clinical characteristics, these patients had relatively larger tumors (4.22±10.47 cm vs. 4.11±11.03 cm, p&amp;lt; 0.001). On multivariate analysis, significant survival benefits were observed for patients treated at HVFs (HR = 0.977, 95% CI 0.973–0.982, p &amp;lt; 0.001). Patients treated at LVFs were significantly less likely to receive radiotherapy (OR = 0.988, 95% CI 0.985-0.992, p &amp;lt; 0.001) as compared to patients treated for intracranial meningioma at HVFs. CONCLUSION Our results indicate that – for patients who underwent treatment for intracranial meningioma during the 15-year study period – treatment recommendations differed and appeared to be associated with a survival disadvantage at LVFs.